Nerve damages by physicogenic causes such as accidents, or nerve damages caused by diseases such as acute ischemic cerebral diseases often causes physical dysfunctions such as motor dysfunctions including paralysis and lalopathy. For example, the number of patients of apoplectic stroke such as cerebral hemorrhage and cerebral infarction is about 1.4 million in Japan. Cerebral nerves are damaged by severe stroke due to the brain hemorrhage or cerebral infraction, which often results in physical dysfunctions such as paralysis and lalopathy as remaining after-troubles.
Moreover, more than one million people in Japan live with some sort of paralysis in their bodies after injury on spinal cord due to traffic accidents and the like, and it has been reported that more than five thousand people with injured spinal cord are annually increased. When rupture, blunt trauma, or compression of the spinal cord is caused by spinal fracture or bruise, spinal nerve is damaged, thereby physical dysfunctions of whole or part of the body occurs, for example, paralysis or motor dysfunction, or sensory dysfunction, autonomic disorder, or dysuria/dyschezia. Since main causes of the spinal cord injuries are traffic and sport accidents, a serious problem has arisen because many young people are bedridden or condemned to live with wheelchairs. For such physical dysfunctions caused by the nerve damage, early rehabilitation is performed as treatment to maintain remaining functions. However, no radical therapy for the physical dysfunctions caused by nerve damage has been developed, and therefore development of an effective therapeutic method has been highly desired.
It has been revealed that the retinoic acid receptor (RAR) present in cellular nucleus, which belongs to the intranuclear receptor super family (Evans, R. M., Science, 240, p. 889, 1988), regulates proliferation and differentiation of animal cells or cellular mortalities via binding with a ligand (Petkovich, M., et al., Nature, 330, pp. 444-450, 1987). A ligand for the RAR that naturally exist in a living body is all-trans retinoic acid (Vitamin A acid) which is an active metabolite of Vitamin A.
It has also been suggested that compounds having retinoic acid-like biological activities (e.g., 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]-benzoic acid: Tamibarotene) also bind to RAR in similar manners to retinoic acid to exhibit their physiological actions (Hashimoto, Y., Cell Struct. Funct., 16, pp. 113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Commun., 166, pp. 1300-1307, 1990). Experimentally by using animals and clinically, these compounds have been found to be useful for therapeutic and preventive treatments of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bone diseases, leukemia, and certain types of cancer.
Vitamin A and its derivatives are known to be involved in the differentiation of nerve cells during fetal and growth periods (Hunter, K. et al., Proc. Natl. Acad. Sci. USA, 88, p. 3666, 1991; Wuarin, L. et al., Int. J. Dev. Neurosci., 8, p. 317, 1990; Haskell, B. E. et al., Cell Tissue Res., 247, p. 67, 1987, Quinn, S. D. P. et al., In Vitro Cell Dev. Biol., 27A, p. 55, 1991) A review article on the effect of retinoic acid to nerves was written by Mey et al. (Mey, J., J Neurobiol., 66, p. 757, 2006).
Mey, however, explains in the above publication that no report was made that clearly demonstrates a therapeutic effect of Vitamin A acid in animals with damaged nerves. For example, in a tibial nerve transaction model, although Vitamin A acid at 50 μL (10 nM RA) induced 30% increase of regenerated nerves, no recovery in nerve and motor functions was reported to be achieved (Taha, M.O. et al., Trabspl. Proc., 36, p.404, 2004). As explained above, it is suggested that Vitamin A acid or RAR signal transmission system is in some way involved in the differentiation of nerve cells. However, it has not yet been clarified whether or not activation of such pathways successfully achieves recovery of motor dysfunction caused by nerve damage. In order to achieve recovery from higher neurological symptoms such as in motor and sensory functions, environmental arrangements around nerve cells including glial cells and neurotrophic factors, as well as the regeneration of neurons, are essential. From the aforementioned findings, it still remains unknown whether or not Vitamin A acid is capable of achieving nerve regeneration and improvement of motor function together with improvement of the aforementioned environments.    Non-patent document 1: Proc. Natl. Acad. Sci. USA, 88, p.3666, 1991    Non-patent document 2: Int. J. Dev. Neurosci., 8, p.317,1990    Non-patent document 3: Cell Tissue Res., 247, p.67, 1987    Non-patent document 4: In Vitro Cell Dev. Biol., 27A, p.55, 1991    Non-patent document 5: J. Neurobiol., 66, p.757, 2006    Non-patent document 6: Trabspl. Proc., 36, p.404, 2004